The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies1. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial2. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear3. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan5. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.
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We thank R. S. Levy-Drummer, C. Wachtel, S. Schwarzbaum and members of the Cohen laboratory for their comments on the manuscript. This study was supported by National Institutes of Health grant 1RO1 GM085022 to Z.B.-J. and by grants from the Israeli Academy of Sciences, the United States - Israel Binational Science Foundation, the Israel Cancer Association, the Koret Foundation, the Israel Cancer Research Fund, the Israel Health Ministry, I-CORE program (41/1), the Israel Science Foundation and the European Research Council to H.Y.C.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-3 with legends, Supplementary Tables 1-4 and 7 (see Separate files for Supplementary Tables 5 and 6), Supplementary Methods and Materials with additional references and a Supplementary Comment. (PDF 6016 kb)
This table shows that all genes significantly changed between female WT vs. male WT (sheet 1), male Transgene vs. male WT (sheet 2), and female Transgene vs. female WT (sheet 3). (XLS 199 kb)
This table contains significantly over-represented Gene Ontology (GO) terms returned by FuncAssociate at an adjusted P-value cutoff of p<0.05. GO terms are listed in descending order of significance for differentially expressed (DE) genes between female WT vs. male WT (sheet 1) and male Transgene vs. male WT (sheet 2). GO analysis for the genes that are intersecting between DE genes in both fWT-mWT and mTG-mWT is listed in the last sheet. (XLS 190 kb)
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Kanfi, Y., Naiman, S., Amir, G. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012). https://doi.org/10.1038/nature10815
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